The long-term objective is to eradicate large well-established solid tumors by adoptively transferred tumorspecific CD8+ T cells. Success depends on CD8+ T cells: (i) eliminating the majority of cancer cells by direct antigen-specific (perforin-dependent) killing and (ii) destroying non-malignant tumor stroma which in conjunction with radiation, chemo- or hormone therapy eliminates cancer cell variants responsible for recurrences. These objectives are obtainable, but have used transgenic CD8+ T cells for adoptive therapy, cancer cells expressing a tumor-specific antigen, tumor-bearing hosts lacking regulatory T cells, and a transplanted tumor model. The challenge is to demonstrate how these conditions will apply (and can be applied) to the elimination of autochthonous tumors in animals and then in patients. Thus, Aim 1 is to determine the requirements and limitations for adoptively transferred T cells to eradicate or arrest large wellestablished tumors. First it will be determined whether adoptively transferred T cells that eradicate large established transplanted tumors can also destroy autochthonous tumors growing in the same host and expressing the same antigen. The capability of the autochthonous tumors to sensitize stroma with antigen released from the cancer cells is also tested. In Aim 2, it will be tested whether stromal sensitization and stromal destruction occurs in different tumor types and whether peripheral T cells can be made effective to destroy tumor stroma by reprogramming these T cells with TCRs from self-reactive poorly lytic T cells. Some cancers harbor sufficient antigen, and in Aim 3, release of this antigen from the cancer cells by therapeutic manipulations will be attempted to load and sensitize the stroma. If cancer cells express too little antigen to sensitize stroma, loading of the stroma with exogenous antigen will be attempted. Finally, by optical imaging of well-established large tumors through a window opening, the real-time sequence of events will be analyzed that occur when adoptively transferred T cells encounter cancer cells and cancer stroma. This may reveal the primary targets of adoptively transferred T cells destroying large established tumors and the mechanisms of cancer variant destruction. These mouse models study novel concepts and use engineered reagents to destroy solid tumors of sizes that are detectable in patients and that escape conventional immunological therapies even in rodents. The plan is to establish principles and to develop novel approaches as a guide for the development of novel therapies to eradicate established solid tumors in patients.